Molecular dynamics and free energy analysis of neuraminidase–ligand interactions

Authors

  • Pascal Bonnet,

    1. School of Pharmacy and Pharmaceutical Sciences, University of Manchester, Manchester M13 9PL, UK
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  • Richard A. Bryce

    Corresponding author
    1. School of Pharmacy and Pharmaceutical Sciences, University of Manchester, Manchester M13 9PL, UK
    • School of Pharmacy and Pharmaceutical Sciences, University of Manchester, Manchester M13 9PL, UK; fax: 44-161-275-2481.
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Abstract

We report molecular dynamics calculations of neuraminidase in complex with an inhibitor, 4-amino-2-deoxy-2,3-didehydro-N-acetylneuraminic acid (N-DANA), with subsequent free energy analysis of binding by using a combined molecular mechanics/continuum solvent model approach. A dynamical model of the complex containing an ionized Glu119 amino acid residue is found to be consistent with experimental data. Computational analysis indicates a major van der Waals component to the inhibitor-neuraminidase binding free energy. Based on the N-DANA/neuraminidase molecular dynamics trajectory, a perturbation methodology was used to predict the binding affinity of related neuraminidase inhibitors by using a force field/Poisson-Boltzmann potential. This approach, incorporating conformational search/local minimization schemes with distance-dependent dielectric or generalized Born solvent models, correctly identifies the most potent neuraminidase inhibitor. Mutation of the key ligand four-substituent to a hydrogen atom indicates no favorable binding free energy contribution of a hydroxyl group; conversely, cationic substituents form favorable electrostatic interactions with neuraminidase. Prospects for further development of the method as an analysis and rational design tool are discussed.

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